ACCESS TO INNOVATIVE TREATMENTS IN MULTIPLE SCLEROSIS IN EUROPE

Transcription

1 ACCESS TO INNOVATIVE TREATMENTS IN MULTIPLE SCLEROSIS IN EUROPE October 2009 A REPORT PREPARED FOR THE EUROPEAN FEDERATION OF PHARMACEUTICAL INDUSTRY ASSOCIATIONS (EFPIA) Gisela Kobelt, PhD MBA Department of Orthopedics, Lund University (Sweden) European Health Economics (France) Gisela.Kobelt@he-europe.com Frida Kasteng, MSc i3 Innovus, Stockholm (Sweden) Frida.Kasteng@i3innovus.com

2 CONTENT Introduction i-ii 1 Burden of Multiple Sclerosis 1:1 1:22 2 Cost of Multiple Sclerosis in Europe 2:1 2:17 3 Uptake of Biologic Treatments 3:1 3:20 4 Determinants of Access to Treatments 4:1 4:24

3 Introduction MS is an inflammatory and neurodegenerative immuno-mediated disorder of the central nervous system, characterized by inflammation, demyelination and primary or secondary axonal degeneration. Clinical manifestations are signs of neurological dysfunctions, e.g. visual and sensory disturbances, limb weakness, gait problems and bladder and bowel symptoms, followed by recovery or by an increasing disability because of irreversible functional disability over time. There are less specific symptoms such as fatigue which interfere both with patients quality of life and productivity, regardless of the degree of disability and disease status. Until the mid-nineties, no therapy was available and treatment was essentially limited to symptomatic relief. When the first disease modifying MS drugs (interferon-beta and glatiramer acetate) were introduced, their price compared to their benefit apparent in clinical trials appeared high and prompted an intense debate whether investment in these treatments represented an efficient use of public resources. The major benefit of treatment, both from a medical and economic point of view, comes from delaying progression to functional disability, and is thus difficult to show in the short or even medium term. As a consequence, the expected value of these new treatments had to be modelled. Early modelling studies of biologics show different results for a number of reasons, the most important being the underlying data, the country of study and the perspective adopted. All models incorporate a number of assumptions, but the paucity of data is more pronounced in some countries and some studies. More importantly, however, reimbursement or health technology assessment agencies in few countries take a societal perspective. In this perspective, all costs regardless of who incurs them the health care system, the patient, society as a whole are taken into consideration. In the case of MS, as for other chronic progressive diseases, it appears difficult to argue that costs outside the health care system should not be considered in the decision making process. Production losses due to temporary and permanent loss of work capacity and the dependency on informal help are a major, if not the largest, part of total costs of the disease. Due of the uncertainty regarding the effectiveness of the treatments and their cost, most countries had protracted reimbursement discussions. However, all countries allowed treatment for patients with relapsing-remitting disease on the health care budget with relatively few restrictions. The reasons were likely the absence of any treatment other than symptomatic interventions, a clearly defined population with a relatively low prevalence ( %) and hence a somewhat limited budget impact. In chronic progressive diseases it is often important to treat as early as possible to maximize the effect on the disease process. MS is no exception and in recent years, treatment after a first clinically isolated symptom has been shown to delay the definite diagnosis of MS. Disease-modifying agents should thus ideally be used as early as possible in the course of the disease, to avoid the development of permanent functional limitations associated with dependence for daily activities and frequently loss of work capacity. This will increase the number of patients on treatment. A number of economic studies have been performed in Europe but no comparative data on how different countries across Europe use the disease modifying drugs exist. i

4 In this report on access to treatment in 30 European countries (27 EU member states plus Iceland, Norway and Switzerland) as well as Turkey, we will address 1) The burden of the disease in terms of epidemiology and the effect on quality of life 2) The cost of the disease in Europe, using a predictive cost model and updated epidemiological and economic data 3) The uptake over time of biologic treatment and the number of patients treated, using available sales data from IMS, adjusted where necessary and possible 4) The conditions and hurdles that affect usage and differences between countries and current knowledge on the value of these treatments, with a focus on parameters that have an economic effect. with the objective to provide material for discussion of how to fully utilize the opportunities created by medical research and innovation. ii

5 Chapter 1 - Burden of Multiple Sclerosis We are grateful for general advice to Jan Hillert, MD PhD (Karolinska University Hospital, Stockholm Sweden). CONTENTS 1 Burden of Multiple Sclerosis...1:1 1.1 Summary...1:1 1.2 Prevalence of MS...1: Literature review...1: Diagnostic criteria and timing...1: Incidence...1: Samples and Reporting...1: North-South Gradient...1: Estimation of Prevalence...1: Approach...1: Calculations...1: Comparison to Published Data... 1: Health Burden... 1: DALYs in MS... 1: QALYs in MS... 1: Disease Symptoms... 1: Health Related Quality of Life... 1: Conclusions... 1: References... 1:21 TABLES Table 1-1 Published data by age and country 1...1:6 Table 1-2 Published data by disease severity 1...1:6 Table 1-3 Published data by gender 1...1:7 Table 1-4 Prevalence rates used for the calculations...1:8 Table 1-5 Prevalence rates and estimated number of patients (>18)... 1:10 Table Total Estimated Number of Patients... 1:14 Table 1-7 Comparison of Estimates to Published Data... 1:15 FIGURES Figure 1-1 Reported prevalence rates 1...1:2 Figure 1-2 Reported (crude) incidence rates 1...1:3 Figure 1-3 Age structures in the different countries (>19)...1:9 Figure 1-4 Estimated Prevalence >19 (cases per 100,000 population)... 1:11 Figure 1-5 Estimated number of patients... 1:12 Figure 1-6- Estimated proportions of patients in different age groups... 1:13 Figure 1-7 The concept of the quality adjusted life year... 1:16 Figure 1-8 The share of morbidity/mortality in the disease burden of MS... 1:17 Figure 1-9 Utilities in different chronic diseases.... 1:18 Figure 1-10 Utility related to disease severity :19 Figure 1-11 Utility loss in MS compared to the normal population... 1:19 Figure 1-12 Rating of disease symptoms... 1:20 Figure 1-13 Impact on HRQoL measured with the SF :21-1:0 -

6 1 Burden of Multiple Sclerosis 1.1 Summary In this chapter we define the burden of Multiple Sclerosis (MS) as the burden for people living with the disease resulting from reduced health (reduced quality of life) and for Society from the number of people affected (prevalence). The economic burden will be discussed in the next chapter. The literature gives conflicting data on the prevalence of MS, with numbers varying from 10/100,000 to 216/100,000 population. Behind this large variation are differences in both the definition of the disease and the populations to which prevalent cases are related to. This represents a difficulty when estimating and comparing the proportion of the patient population on treatment with innovative treatments in different countries. We therefore propose a standardized way of estimating prevalence, using data from countries where prevalence by age groups is available. With this method, we estimate the prevalence in the European population >19 to be 118/100,000 (0.12%), with a total number of patients>19 in Europe (defined as EU27 plus Iceland, Norway and Switzerland) of 470,000. Applied to the total population, prevalence would be estimated a 93/100,000 (0.09%). Our purpose is to arrive at a prevalence rate that can be used to estimate the total burden of the disease Europe and to analyze the uptake of new drugs and the share of patients treated. The burden on patients - expressed as utility, a preference-based quality of life index anchored between 0=death and 1=full health - is one of the heaviest (with low utilities) among chronic progressive diseases. The average utility has been estimated at around , but most importantly, in decreases from values close to normal to values below 0.1 as the disease progresses to severe health states with severe impairment. It is thus very important to have good estimates of the prevalence of patients with severe disease where the burden is largest. On average, a population of MS patients looses around QALYs per year at all age, compared to the normal population. From the available data we can estimate that the total burden of MS in Europe in terms of QALYs lost per year is ,000. Of these, 65,000 QALYs are lost for mild disease (55% of patients), 41,000 for moderate disease (25% of patients) and 30,000 for severe disease (20% of patients). - 1:1 -

7 1.2 Prevalence of MS Literature review The prevalence of MS has generally been estimated at % of the adult population, with an average of 83/100,000 over the past three decades, but ranges from 10/100,000 to 216/100,000 has been reported in published studies 1. Similarly, incidence ranged from 0.5/100,000 to 12/100,000 of the adult population, with a mean estimated at 4.3/100, An in-depth review of almost 200 published studies was performed in 2002 and updated in 2006, highlighting the differences 1, 2, as shown in Figure 1-1, but no attempt was made to adjust or extrapolate the numbers to different countries. Nevertheless, we base most of our comments on this review by Pugliatti and colleagues. Figure 1-1 Reported prevalence rates 1 Numbers in brackets indicate crude rates Reprinted with permission from Eur J Neurol 2006 volume 13 1 Although rates may indeed be different between different populations and countries, this large range is likely due to the quality and methodology of the studies performed, age groups included, reporting of crude or adjusted rates, as well as the timing of the study. Indeed, one could expect that diagnosis has been improved particularly in the last decade, with the availability of effective treatments. It is thus difficult to directly derive an estimate of the number of prevalent patients in the different European countries. However, this is a prerequisite to estimating the total cost of MS in Europe, analyzing the uptake of the biologics and evaluating the proportion of patients on treatment. We therefore first discuss the issues related to the published literature and the difficulty to draw conclusions on the prevalence rates in the different countries, and then propose an approach to estimating European prevalence. - 1:2 -

8 Diagnostic criteria and timing MS is and inflammatory and neurodegenerative immuno-mediated disorder of the central nervous system, characterized by inflammation, demyelination and primary or secondary axonal degeneration 3. Clinical manifestations are signs of neurological dysfunctions, e.g. visual and sensory disturbances, limb weakness, gait problems and bladder and bowel symptoms, followed by recovery or by an increasing disability because of irreversible functional disability over time 4. There are less specific symptoms such as fatigue which interfere both with patients quality of life (QoL) and productivity, regardless of the degree of disability and disease status 5. The majority of epidemiological studies used the Poser criteria to define MS 6. However, these criteria define patients as clinical definite MS or clinically probable MS, which thus may lead to differences in studies. More recently, magnetic resonance imaging (MRI) has been incorporated into diagnostic criteria 7, and the new criteria are currently used more often, e.g. in clinical trials. Compared to the Poster criteria, prevalence rates appear higher when using McDonald criteria 8. As a consequence, it may be expected that reported prevalence is increasing over time, but it is difficult to establish a time trend in available studies. Nevertheless, three studies from Norway reported increasing rates with time: 74/100,000 in 1993, 121/100,000 in 1995 and 165/100,000 in Similarly, two studies in northern Italy reported 69/100,000 in 1993 and 81/100,000 in In western Poland rates increased from 45/100,000 in 1981 to 55/100,000 in A study in a French region (Lorraine) found that age-adjusted prevalence increased between It is clearly impossible to verify whether this trend is due to better diagnosis or simply a consequence of the study methodology, and this is not our objective. Rather we want to highlight possible causes for the wide range of prevalence rates reported Incidence Figure 1-2 Reported (crude) incidence rates 1 Reprinted with permission from Eur J Neurol 2006 volume :3 -

9 When comparing incidence to prevalence, the variation in reported prevalence does not seem to be supported. The incidence rate reported for Poland is 2.2/100,000 and for France 4.3/100,000, yet prevalence rates are reported as 50 and 55/100,000, respectively. Spain and Rumania have similar prevalence estimates (36-55/100,000 and 41/100,000, respectively) yet incidence is reported as 3.8/100,000 in Spain and 0.2/100,000 in Romania. Population survival rates are higher in France and Spain compared to Poland and Rumania and these numbers appear thus questionable. Differences are also reported in countries that are apparently more similar. In the Nordic area, Norway reports an incidence of 8.7/100,000, Sweden of 5.2/100,000 and Finland 5.1/100,000 - yet, prevalence is reported as 120/100,000, 153/100,000 and 93/100,000, respectively. Germany and France report similar incidence rates (4.2/100,000 and 4.3/100,000, respectively) yet prevalence is estimated at 83/100,000 and higher in Germany and 50/100,000 in France. Again, it is not the objective of this report to evaluate or criticize epidemiological data in detail, but we conclude that incidence and prevalence data reported do not seem to match Samples and Reporting Published studies have included different populations or have been performed in different geographic areas within countries, and some findings were surprising. For instance rates within Italy vary from 61/100,000 to 140/100,000. Rates in the United Kingdom range from 103/100,000 to 186/100,000. Only four studies included a nationwide sample: Austria (1999), Denmark (1996), France (1986) and Iceland (1999). Other studies included between less than 1% of the country s population up to 30%, with most however limited to less than 10%. The influence of this on the findings is difficult to judge. But while it is generally accepted that there are differences between and within countries, we would argue that the magnitude of the differences reported appears unlikely to be true. Studies may also have included samples with a different age structure. In particular, prevalence in the population above 65 years appears difficult to establish and published rates vary between 0/100,000 and 313/100,000. Furthermore prevalence for this particular age group is often stated as approximate only, and some studies may simply not have included it. It is striking to observe that rates for the group between 65 and 75 years in the Nordic area are very high, and in the Mediterranean area very low: Spain reports 8/100,000 while Scandinavian countries report rates around 200/100,000. Differences in the same magnitude are reported for the population over 75 years. We argue that this is likely due to differences in diagnosis over time, where more focus has been put on MS diagnosis in Northern Europe for a long time, resulting in patients diagnosed 3 decades or more age arriving in these older age groups today. One could indeed expect that over the next 2 decades these differences might disappear, as the new treatments enhance the focus on diagnosis across European countries. Finally, many studies report data without adjusting to population age and gender distribution, and overall figures may thus not be fully accurate. - 1:4 -

10 North-South Gradient It is commonly accepted that prevalence is higher in Northern Europe than in Southern Europe, although it is difficult to understand where the separation line should be. Do countries like Austria, Germany and Switzerland belong to the North? If so, how should then France be classified, Northern or Mediterranean? If the former belong to the North, how different are then prevalence rates from the true Northern countries, Scandinavian countries and the United Kingdom? And why would Finland have rates similar to Germany rather than to Sweden and Norway? Also, purely in terms of latitude, the Baltic States would be classified as Northern, yet their rates are similar to the Mediterranean area or even lower Considering this, we find it difficult to classify countries into North-South groups. Rather, as Pugliatti and colleagues, we would argue again that this apparent geographic trend is predominantly due to better diagnoses earlier in some countries and better accuracy of epidemiological survey methodology. Nevertheless, a certain heterogeneity appears to exist between different population groups, e.g. very high rates in Scotland, Northern Norway, or Sardinia Estimation of Prevalence Approach The issues discussed above may not be problematic when considering one country at a time, or when simply reviewing existing literature. However, in this report, we build the estimate of the cost of MS in all European countries on three types of data: the mean cost per patient based on available cost analyses adjusted for economic factors, total sales of biologic drugs in each country, and prevalence. The latter is a crucial input, as it is used to estimate the proportion of patients treated in each country to calculate the mean drug cost per prevalent patient, and to extrapolate the mean cost per patient to total national and European costs. In a previous economic paper 10 we based our cost estimates on the prevalence rates for each country as summarized by Pugliatti and colleagues. However, in view of the issues discussed above, we now argue that prevalence might be more similar across Europe, and that the considerable differences observed could be to some extent a consequence of - the timing of the study (due to changes in diagnostic criteria and focus on rapid correct diagnosis) - the region of observation (urban, rural; economic situation of the area) - the study methods (design, sample, age adjustment) - the age structure of a country (proportion of patients over 65) - medical tradition and access to specialists for diagnosis. We therefore propose to use a more general calculation to estimate diagnosed prevalence in the adult population, using the following approach: 1. Part of the variation in prevalence is due to the age structure, i.e. prevalence will be higher in countries with a larger population of elderly Consequently, we used prevalence rates for 5 different age-groups throughout our calculations (20-34, 35-49, 50-64, 65-74, 74+) and applied population numbers to age specific prevalence rates. These age groups allow a more refined estimate and also differential cost analysis particularly in terms of workforce participation and mean salary. The cut-off at age 20 is justified by the way population data are generally reported. - 1:5 -

11 Table 1-1 Published data by age and country 1 Reprinted with permission from Eur J Neurol 2006 volume Also in view of the cost estimates, it is important to take into account disease severity. A large number of studies have shown the steep increase in costs between mild and severe disease 11. Most often studies have reported costs for mild, moderate and severe disease, using the EDSS (Expanded Disability Status Scale 12 ) to define groups. Definitions have varied somewhat, but we used the definition published in a recent series of observational studies 11 : EDSS <4, 4-6.5, >6.5. A number of epidemiological studies have reported detailed data on the severity distribution 1, and we estimated the mean proportions to be 55%, 25% 20%, respectively, for the groups defined above. Table 1-2 Published data by disease severity 1 Reprinted with permission from Eur J Neurol 2006 volume :6 -

12 3. For cost estimates, prevalence is required by gender, as health care consumption, but most importantly workforce participation and income differs between men and women. Similar to overall numbers, the women to men ratio in published studies varies greatly as well, from 1.1 to 3.4 1, which we would argue to be due to sample selection. On average the proportion of men reported is however around 30-35% and we hence use a women to men ration of 2 (67% women, 33% men) for our calculations. Table 1-3 Published data by gender 1 Reprinted with permission from Eur J Neurol 2006 volume Costs are further influenced by the age distribution within these three EDSS groups, particularly the proportion of patients above 65 for which indirect costs are excluded. We used patient data from a French epidemiological cohort in Lyon prior to the use of disease modifying drugs 13, 14 as well as data from the Stockholm MS registry 14 to estimate the mean age in the three EDSS groups. Both these cohorts represent a large proportion of patients in their defined area and can thus be considered population based. In the mild group, the mean age was 37 years, in the moderate group 45 years and in the severe group 48 years. - 1:7 -

13 5. Finally, countries were grouped into 5 clusters, based on similarity in geographical situation, ethnic groups and published findings by age. This also allowed accounting for the differences in prevalence due to medical tradition (earlier and more accurate ascertainment of diagnosis). Even if true prevalence was higher than found in some of these studies, it is only those patients actually diagnosed that are candidates for receiving the new disease modifying treatments Calculations The table below shows the country groupings and age-specific prevalence rates used in our calculations. These rates were then applied to the age structure of the individual countries and the number of prevalent patients per age group and in total estimated. Table 1-4 Prevalence rates used for the calculations Group Countries Prevalence >19 (per 100,000) by Age Groups * 1 Denmark, Finland, Germany, Iceland, Ireland, Norway, Sweden, United Kingdom Austria, Belgium, Luxembourg, Netherlands, Switzerland Czech Republic, France, Hungary, Italy, Portugal, Slovenia, Spain Cyprus, Estonia, Greece, Latvia, Lithuania, Malta, Poland, Slovakia Bulgaria, Romania, Turkey *Expected number of currently diagnosed patients >19 per 100,000 The results were then compared to the published studies and also other sources of data. In particular, the MS International Federation has published an Atlas of MS across the world that contains prevalence and incidence data ( Upon closer examination, most of the numbers in the MS Atlas come as expected from the published studies and are hence already taken into account in our estimates. A few countries without own studies used the highest available prevalence rates for their estimates. We have chosen to ignore the differences between these numbers and our results, as for the purpose of this report we are interested in diagnosed patients, not in potentially underlying prevalence. A detailed comparison of the differences can be found at the end of this chapter. - 1:8 -

14 Figure 1-3 Age structures in the different countries (>19) Age structure in Europe (>19) Turkey Ireland Cyprus Slovakia Iceland Spain Romania Luxembourg Poland Lit huania Czech Republic Port ugal Austria Slovenia United Kingdom Norway Lat via Greece Netherlands Estonia Swit zerland Hungary Malta France Bulgaria Denmark Belgium Italy Germany Sweden Finland 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >64-1:9 -

15 Table 1-5 Prevalence rates and estimated number of patients (>19) Country Population Patients Prevalence Prevalence >19 >19 >19 per (000 ) per 100, ,000 population Austria 6,485 7, Belgium 8,113 9, Bulgaria 6,158 2, Cyprus Czech Republic 8,126 8, Denmark 4,104 6, Estonia 1, Finland 4,039 6, France 47,375 47, Germany 66, , Greece 8,960 6, Hungary 7,904 7, Iceland Ireland 3,099 4, Italy 47,717 47, Latvia 1,786 1, Lithuania 2,576 2, Luxembourg Malta Netherlands 12,380 14, Norway 3,451 5, Poland 29,207 22, Portugal 8,355 8, Romania 16,610 8, Slovakia 4,105 3, Slovenia 1,604 1, Spain 35,424 35, Sweden 6,916 11, Switzerland 5,852 6, United Kingdom 45,871 76, Turkey 44,823 24, :10 -

16 The average prevalence in the population over 19 years for Europe 27+3 (excluding Turkey) was estimated at 0.13%. Applied to the total population, the prevalence rate would be 0.093%. Although our estimates focus on actually diagnosed cases, we believe that after the developments in the MS field (several new drugs, better diagnostic tools, earlier diagnosis) these rates appear acceptable. Figure 1-4 Estimated Prevalence >19 (cases per 100,000 population) MS prevalence (per 100,000) >19 Finland Germany Denmark Sweden United Kingdom Norway Iceland Ireland Netherlands Switzerland Luxembourg Austria Belgium Slovenia France Hungary Portugal Czech Republic Italy Spain Cyprus Lithuania Slovakia Poland Latvia Est onia Malta Greece Turkey Romania Bulgaria :11 -

17 Figure 1-5 Estimated number of patients Number of MS cases by age groups - large countries Germany United Kingdom France Italy Spain Turkey Poland 0 20,000 40,000 60,000 80, , , Number of MS cases by age groups - smaller countries Net herlands Sweden Belgium Portugal Romania Czech Republic Hungary Austria Denmark Switzerland Finland Greece Norway Ireland Slovakia Bulgaria Lithuania Slovenia Latvia Estonia Cyprus Luxembourg Iceland Malta 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 16, :12 -

18 Figure 1-6- Estimated proportions of patients in different age groups Proportion of MS cases by age groups Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Lat via Lit huania Luxembourg Malta Net herlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden Swit zerland Turkey United Kingdom 0% 20% 40% 60% 80% 100% Using our model, the total number of diagnosed patients was estimated at 470,000 in Europe (EU27+3), of which 410,000 in Western Europe (old EU15+3) and 60,000 in Central/Eastern Europe (new EU markets). - 1:13 -

19 Table Total Estimated Number of Patients Number of patients by age groups Total EU , , ,500 53,000 19, ,000 W.Europe (EU15+3) 57, , ,000 49,500 18, ,000 E.Europe (new EU) 14,500 26,000 14,500 3, ,000 Turkey 8,800 12,700 3, , Comparison to Published Data As discussed above, our estimates differ somewhat from published data, because we used similar rates across groups of countries to compensate for study and population differences we applied age specific rates to country populations to overcome the different reporting of crude and adjusted rates we used somewhat higher rates than reported in some countries with the rationale that in the last one or two decades prevalence has increased due to better and earlier diagnosis we largely ignored incidence rates as these often did not correspond to expected prevalence. The comparison to the MS Atlas published by the International MS Society (MSIF) shows that most estimates were based on published rates or on the higher range of available prevalence rates in countries with no studies. Also prevalence rates and the number of patients do not always correspond. In a number of countries, our estimates are thus lower than the Atlas but close to published rates. A special comment has to be made regarding Portugal. Published rates for Portugal are low, but similar to published rates for Spain. The number of patients indicated in the MS Atlas for Portugal is according to published rates, but much higher than published rates for Spain. When calculating the number of patients treated using actual IMS sales data and the published prevalence, we found that the vast majority of patients would be on treatment (i.e. a higher % than in any other European country). This appeared not reasonable and we hence adjusted the prevalence to the rates used for Spain. - 1:14 -

20 Table 1-7 Comparison of Estimates to Published Data Country Cases per 100,000 population Total cases Literature 1 MS Atlas Our estimates (population) Our estimates (population >19 years) MS Atlas (total cases) Our estimates (cases >19) Austria ,000 7,685 Belgium ,093 9,516 Bulgaria ,000 2,930 Cyprus Czech Republic ,000 8,113 Denmark ,500 6,997 Estonia , Finland 93,107, ,000 6,924 France ,000 47,626 Germany 83, , ,120 Greece ,000 6,668 Hungary ,000 7,928 Iceland Ireland 121, ,000 4,896 Italy 53,58,69,81, ,000 47,608 Latvia ,500 1,374 Lithuania ,629 2,027 Luxembourg 73,120, Malta Netherlands ,000 14,872 Norway 73,120, ,000 5,741 Poland 45, ,000 22,469 Portugal ,000 8,381 Romania ,000 8,159 Slovakia ,400 3,211 Slovenia ,000 1,622 Spain 32,43, ,000 35,214 Sweden ,000 11,590 Switzerland ,000 6,971 Turkey ,000 24,940 United Kingdom 97,107,168, 184, ,000 76,851-1:15 -

21 1.3 Health Burden Health burden is defined here as the impact on patients health related quality of life and their ability to perform daily activities. On a macro-level, where one of the key requirements is comparability across diseases, the health burden is generally measured by disability-adjusted lifeyears (DALY), a two-dimensional measure integrating mortality and disability (morbidity) developed by the World Health Organization (WHO) 15. In simple terms, one DALY can be thought of as one year without disability lost. The measure does thus not include health related quality of life, but is based on disability. In health economic studies, the quality-adjusted life-year (QALY) is preferred. As the DALY, it is a two-dimensional measure, combining life-years with a weight (called utility) between 0 (representing death) and 1 (representing full health) that represents the population s preference for given health states 16. The major differences of the QALY to the DALY are that utility does incorporate health related quality of life and that 0 and 1 are clearly anchored with reference values established with the general population. As shown below, the weighting of life-years with their quality allows comparing the effect of treatments that predominantly improve health related quality of life (e.g. in MS) to treatments that predominantly affect survival (e.g. in cancer). Living 2 years with a utility of 0.5 results in 1 QALY - which is the same as living 1 year in full health (utility 1.0). Figure 1-7 The concept of the quality adjusted life year UTILITY VALUE QALY QALY 0.5 QALY YEARS - 1:16 -

22 1.3.1 DALYs in MS The loss of DALYs is thus composed of two inputs, mortality (years of life lost) and disability (years of disability), and to compare across diseases, it is interesting to investigate which part contributes most to the measure. For the total burden of disease in Europe, the split between years of life lost and years of disability is approximately 50%-50% as shown in the figure below 15. However the distribution between disability and mortality to the disease burden varies greatly depending on the type of disease. The entire burden of migraine comes from disability, and for RA the burden due to premature mortality is limited. For MS, the impact on mortality has been highlighted in recent years, in particular with data from the Danish population-based MS registry 17. The most recent DALY estimates by WHO attribute around one third of the health burden of MS to premature mortality, despite the severe disability that most patients experience. One reason for this is that the onset of MS is very early. Figure 1-8 The share of morbidity and mortality in the disease burden of MS Disability and mortality contribution to the total disease burden for selected diseases in Europe* disability mortality All Causes Migraine Rheumatoid arthritis Multiple sclerosis Diabetes mellitus HIV/AIDS Cardiovascular diseases Malignant neoplasms 0% 20% 40% 60% 80% 100% *WHO sub-region EUR A (Andorra, Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, Norway, Netherlands, Portugal, San Marino, Slovenia, Spain, Sweden. Switzerland, United Kingdom) - 1:17 -

23 1.3.2 QALYs in MS QALYs have been widely used and accepted for economic evaluation in MS. As the disease manifests itself with a number of different symptoms sensory disturbances, limb weakness, gait problems, neurogenic bladder and bowel symptoms - and irreversible functional disability and premature mortality, a measure that combines the impact on quality of life and life expectancy appears the most appropriate tool to evaluate of the burden of the disease and the health gain with treatment. Compared to many other chronic diseases, mean utility in MS is low, as shown in Fig 1-9 below. More importantly, though, a considerable number of studies have shown that it decreases rapidly right from the onset of the disease 14, Indeed, it is most astonishing how similar utilities related to disability are across European countries when measured with the same instrument (the EQ-5D 19 ) in studies using the same methodology 20 (Fig 1-10). In MS, mean utility is thus strongly influenced by the disease severity of the sample, and small samples may produce biased results. This can be observed in a study that used interview techniques to assess utilities and thus necessarily enrolled a small sample only 21. Utility is closely correlated with disability, expressed on a scale between 0 and 9 with the Expanded Disability Status Scale (EDSS) 12. Although the EDSS focuses strongly on ambulation and may not capture the mental disability to its full extent, it has been shown to be highly correlated not only with utility, but also costs. It is hence not surprising that the QALY is the measure of choice to assess the effect of treatment. Figure 1-9 Utilities in different chronic diseases. Disease Mean utility Sample size Other rheumatoid arthritis Rheumatoid arthritis Multiple sclerosis Angina pectoris Acute myocardial infarction Atrial fibrillation and flutter Chronic ischaemic heart disease Gastro-oesophageal reflux disease Crohn's disease (regional enteritis) Essential (primary) hyptertension Malignant neoplasm of prostate Non-insulin-dependent diabetes Ulcerative colitis Source: adapted from Curry et al, Value in Health :18 -

24 Figure 1-10 Utility related to disease severity 20 MS - Utility by Disability Level Utility / /9 EDSS Austria Belgium Germany Italy Netherlands Spain Sw eden Sw itzerland UK Source: Adapted from 20 Utility was measured in all studies using the EQ-5D 19. When mean utilities of patients with MS are compared to those of an agematched sample of the general population, as illustrated in Fig 1-11 for Germany, the loss of QALYs can be estimated at around 0.3 QALYs per year, or expressed differently, a 30% loss of quality of life (adapted from 22 ) Figure 1-11 Utility loss in MS compared to the normal population Normal population Mean utility MS patients Loss of utility Mean EDSS Age groups Note: Example: German women - 1:19 -

25 From these available data, it is possible to estimate the total burden of MS in Europe in terms of QALYs lost. Using a simplified estimate based on the average loss of 0.3 QALYs per year above and the total number of patients, we can estimate the total burden as approximately 140,000 QALYs lost every year, the majority (88%) in Western Europe. Using estimates of mild, moderate and severe disease prevalence, and average age in these groups from the Stockholm MS registry, the total loss of QALYs for mild disease is 65,000 QALYs, for moderate disease 41,000 QALYs and for severe disease 30,000 QALYs, leading to a total loss of 136,000 QALYs per year Disease Symptoms As discussed above, EDSS may not capture all the difficulties patients with MS experience. In a recent survey in France 14 participants were asked to indicate the symptoms, activities of daily living and other issues that were most affected by the disease or posed the greatest problems for them. Of the 1355 participants, 1349 answered the question. Fatigue represented a problem for almost all patients (84%), followed by anxiety regarding the evolution of the disease (63%), and ambulation, balance, bowel/bladder symptoms and sensory/motor disturbances for 40-50% of patients. (Data on file, personal communication G.Kobelt and Ligue Française pour la Sclérose en Plaque). Figure 1-12 Rating of disease symptoms Patient-reported difficulties 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% Fatigue Anxiety Ambulation Balance Bladder/bowel Sensory/motor Memory Household duties Pain Leisure activities Vision Psychological Treatments Lack of understanding Discouragement Financial difficulties Professional activities Isolation Lack of interest Child care - 1:20 -

26 Source: data on file, adapted from Health Related Quality of Life Nevertheless, physical disability remains the major impact on patients healthrelated quality of life (HRQoL). An early study in Canada evaluated the effect of the disease on HRQoL 23. The study used a generic QoL questionnaire, the SF36 24 and compared scores of MS patients to those of an age and gender matched normal population. We illustrate the results below for the patient group with moderate disease (EDSS ). As can be seen in Figure 1-13, the largest decrement in HRQoL occurs indeed in the two physical domains of Physical Function and Physical Role Fulfillment. Figure 1-13 Impact on HRQoL measured with the SF MS EDSS 3-6 Normals Physical Function Role Physical Bodily Pain General Health Vitality Social Fonction Role Emotional Mental Health 1.4 Conclusions This chapter summarizes the literature on prevalence of MS and the impact the disease has on patients. The data on the health burden are among the best documented, with a series of large surveys across Western Europe. The data on prevalence are more difficult to interpret and we have therefore proposed an approach to estimating prevalence from existing detailed data sets. The results yields the prevalence for patients that are diagnosed rather than the estimated potential number of patients, as this is more relevant when estimating the proportion of patients that receive treatment. 1.5 References 1. Pugliatti M, Rosati G, Carton H, et al. The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006;13(7): Pugliatti M, Sotgiu S, Rosati G. The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg 2002;202: :21 -

27 3. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338(5): Ebers G. Natural history of multiple sclerosis. New York: Churchill Livingston; Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol 1988;45(4): Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13(3): McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1): Fangerau T, Schimrigk S, Haupts M, et al. Diagnosis of multiple sclerosis: comparison of the Poser criteria and the new McDonald criteria. Acta Neurol Scand 2004;109(6): Debouverie M, Rumbach L, Clavelou P. [The organisation of health care and epidemiology of multiple sclerosis in France]. Rev Neurol (Paris) 2007;163(6-7): Sobocki P, Pugliatti M, Lauer K, Kobelt G. Estimation of the cost of MS in Europe: extrapolations from a multinational cost study. Mult Scler 2007;13(8): Kobelt G, Berg J, Lindgren P, et al. Costs and Quality of Life of Multiple Sclerosis in Europe. J Neurol Neurosurg Psychatry 2006;77(8): Kurtzke J. Rating neurological impairment in multiple sclerosis and expanded disability status scale (EDSS). Neurology 1983;33(11): Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343(20): Kobelt G, Richard-Texier B, Lindgren P. The cost of multiple sclerosis in France and potential changes with disease modifying interventions. J Multiple sclerosis 2009;in print (on-line mid March WorldHealthOrganisation. Dearth and DALY estimated for 2002 by cause for WHO member states. In: WHO, Geneva; Torrance G. Measurement of health state utilities for economic appraisal. A review. Journal of Health Economics 1986;5: Koch-Henriksen N. The Danish multiple sclerosis registry: a 50-year followup. Multiple Sclerosis 1999;5: Kobelt G, Berg J, Lindgren P, et al. Costs and quality of life of multiple sclerosis in Austria. Eur J Health Econ 2006;7 Suppl 2:S The EuroQol Group. EuroQol - a new facility for the measurement of healthrelated quality of life. Health Policy 1990;16: Kobelt G, Berg J, Lindgren P, et al. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry 2006;77(8): Prosser L, Kuntz K, Bar-Or A, Weinstein M. Cost-effecrtivness of interferon beta-1a, interferon beta-1b and glatiramer acetate in newly dianosed nonprimary progressive multiple sclerosis. Value in Health 2004;7((5)): Kobelt G, Berg J, Lindgren P, et al. Costs and quality of life of multiple sclerosis in Germany. Eur J Health Econ 2006;7 Suppl 2:S Canadian Burden of Illness Group. Burden of Illness in Multiple Sclerosis. Part II: Quality of Life. In; 1998: Ware J, Sherbourne C, McHorney C. The MOS 36-Item Short Form Health Survey. Medical Care 1993;31( ). - 1:22 -

28 Chapter 2 - Cost of Multiple Sclerosis CONTENTS 2 Cost of Multiple Sclerosis in Europe Summary The economic burden of Multiple Sclerosis Findings in early studies Findings in recent studies Modelling the Cost of MS Model design Model data Results Conclusion References TABLES Table 2-1 Cost differences due to perspective and calculation methods Table 2-2 Cost differences due to data collection methods Table 2-3 Description of samples in the European Survey of Cost of MS Table 2-4 Studies included in the model calculations Table 2-5 Price levels in health care an health expenditure per capita 23, Table 2-6 Labour costs and employment rate by age Table 2-7 estimated annual cost of MS by country, total Table 2-8 Mean estimated annual cost per patient ( 2008) FIGURES Figure 2-1 Mean annual costs per patient by level of disease severity 12, Figure 2-2 Mean annual cost per patient with MS ( 2008) Figure 2-3 Costs by age groups (excluding biologics) Figure 2-4 Structure of Costs (EU27 + 3) Figure 2-5 Structure of Costs (Western and Central/Eastern Europe)

29 2 Cost of Multiple Sclerosis in Europe 2.1 Summary In this chapter, we estimate the total cost of Multiple Sclerosis (MS) in Europe, based on the cost per patient and on the prevalence of diagnosed patients. Multiple sclerosis (MS) is one of the diseases with the most extensive research on costs and quality of life. In Europe, a number of large studies have been performed, many studies on certain of the economic aspects exist, and review papers have been published. The most recent literature on the cost of MS includes a series of comprehensive cost analyses covering ten countries including around 15,000 patients, by the same research group. Since these analyses all use the same methodology and are consistent in their approach, they are a good basis for a European-wide analysis of the cost of MS. We used and refined a previously developed cost-model to estimate total costs of MS in Europe. Since costs increase with increasing disease severity, the earlier model had stratified costs into three severity groups using a functional scale (EDSS). In our current analysis we use instead age-groups as the main parameters, to account for a different prevalence at different ages, different disease severity levels over time as well as different costs due in particular to differences in work force participation and income. Within these age groups, costs were then re-stratified according to the severity distribution in the study series. The age groups in the model are the same as in the calculation of prevalence in the previous chapter, except for the fact that all patients above 65 are combined into one group. Costs were estimated as proportional costs for the different types of resources (health care, non-medical costs, production losses and informal care). We used economic indicators to impute costs for countries without published data for all cost categories except for the disease modifying treatments. There are considerable differences in the use of these drugs across Europe, and imputation is therefore less feasible. The cost of the biologic drugs was thus directly extracted from international sales data. The average cost per patient with MS in Europe was estimated at 36,000, with as expected a clear difference between Western Europe ( 39,000) and Central/Eastern Europe ( 11,600). The total cost of the disease was estimated at 15 billion, of which slightly over 14 billion occur in the old EU countries with 410,000 MS patients and 650 million in the new EU countries in Central and Eastern Europe with 60,000 diagnosed patients. The majority of costs are outside the health care system: Health care costs are estimated at a mere 32% of total costs, of which biologics represent around one third. Non medical costs are estimated at 10%, informal care at 22% and production losses at 36% of all costs.. These estimates are somewhat higher than what was previously found. The annual cost per patient is however similar, considering overall cost increases over time. The overall cost is higher, due to refined and higher prevalence and cost estimates. 2-1

30 2.2 The economic burden of Multiple Sclerosis Information about the cost of a disease provides important general information to policy makers, but can not be used directly for decisions about resource allocation to individual treatments. Cost-of illness studies do, however, constitute important data that can serve as a basis for cost-effectiveness analyses of health interventions. Presenting an overall picture of costs will also facilitate the interpretation of ad-hoc studies that only focus on specific cost items or situations (e.g. payer versus social perspective). The economic burden of a disease is a complement to information about the health burden. Multiple sclerosis (MS) is one of the diseases with the most extensive research on costs and quality of life. In Europe, a number of comprehensive studies have been performed, many studies on certain of the economic aspects exist, and review papers have been published 1-3. We will therefore not provide a further in-depth review of these studies but only summarize study findings and issues related to their interpretation briefly. The considerable cost, both to the health care system and to society, of MS as a chronic progressive and disabling disease has been recognized for a long time. Estimating the precise costs incurred due to a disease is difficult and cost-of-illness estimates are thus often surrounded with a certain degree of uncertainty. A number of factors influence the results, such as the country where the study has been performed, the study objectives, the samples included, prevalence estimates, and not the least the methodology used 2. Major methodological issues in cost of illness studies pertain to how costs due to the disease can be separated from other unrelated costs patients may incur, what perspective is adopted for the analysis, a societal perspective (all costs regardless of who pays) or a payer perspective (only costs carried by the health and care and social systems). The largest differences will occur due to the perspective, but even within the studies using the same perspective large differences may arise due to the method of calculation, in particular the way production losses are valued; the human capital approach uses the wage rate as a proxy for an individual s productivity for the entire duration, while the friction cost method assumes that any person on sick-leave or early retirement will be replaced within 4 months and no loss will occur. Table 2-1 Cost differences due to perspective and calculation methods Perspectives Germany Calculation Method Netherlands Societal perspective Annual cost per patient (N=1549; 2005) 5 Annual cost per patient (N=2973; 2005) 4 Public payers Societal Human Capital Friction Cost Method Method Mean Mean Mean Mean Health care costs Non-medical costs Production losses Total annual cost ) Inpatient and outpatient care; 2)Investments, services, transport, informal care; 3) Production losses, patients <65 2-2